Likely inborn error of metabolism

Gene: HSPA9

Green List (high evidence)

Comment on mode of inheritance: As reviewed previously, there are more than 3 unrelated cases are reported with biallelic HSPA9 variants and EVEN-PLUS syndrome. There are also several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants and CSA (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Both EVEN-PLUS syndrome and Sideroblastic anemia stem from mitochondrial dysfunction. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update.

Created: 2 Sep 2026, 3:40 p.m. | Last Modified: 2 Sep 2026, 3:40 p.m.

Panel Version: 9.30

PMID: 26491070 Schmitz-Abe et al., 2015
Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected.
Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals.

Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (pC487Sfs*3 & p.E577K in Family K; p.V296* & ?p.203_204ins3 in family L).
In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype".
The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). This variant has MAF = 0.8085 in East Asian population.
2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance.
FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR).

PMID: 30401706 Ducamp & Fleming, 2018 review
"a small minority of patients have the more prevalent, ancestral rs10117C allele in trans of a null or severe missense variant, suggesting the possibility that the rs10117T variant is in linkage disequilibrium with the “true” causative variant"

PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 36094340 Watanabe et al., 2023
Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a homozygous SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants:
Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans.
Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls.
Described as pseudodominant inheritance.

Functional: PMID: 25550197 Krysiak et al., 2016
Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.

Created: 2 Sep 2026, 3:39 p.m. | Last Modified: 2 Sep 2026, 3:39 p.m.

Panel Version: 9.30

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Anemia, sideroblastic, 4, OMIM:182170; sideroblastic anemia, MONDO:0015194; Even-plus syndrome, OMIM:616854; even-plus syndrome, MONDO:0014801

Publications

• 25550197
• 26491070
• 30401706
• 33398880
• 36094340
• 38360212

Green List (high evidence)

Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.

Created: 10 Nov 2023, 3:36 p.m. | Last Modified: 12 Nov 2023, 12:54 p.m.

Panel Version: 4.74

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Even-plus syndrome, OMIM:616854

Green List (high evidence)

>3 independent cases now reported
PMID: 26598328 describes the identification of biallelic variants in HSPA9 in three patients (two of which are siblings), with EVEN-PLUS syndrome
PMID: 32869452 reported another patient
PMID: 35779070 reported two siblings
PMID: 36052765 reported first Chinese patient

Created: 2 Nov 2023, 9:08 a.m. | Last Modified: 2 Nov 2023, 9:08 a.m.

Panel Version: 4.55

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Even-plus syndrome 616854

Publications

• 26598328
• 32869452
• 35779070
• 36052765

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 4 May 2024, 3:17 p.m. | Last Modified: 4 May 2024, 3:17 p.m.

Panel Version: 5.3

Comment on phenotypes: EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia;Epiphyseal, Vertebral, Ear, Nose, plus associated findings.
Monoallelic variants reported in Anemia, sideroblastic, 4 182170.

Created: 30 Sep 2019, 1:35 p.m. | Last Modified: 30 Sep 2019, 1:35 p.m.

Panel Version: 1.330

Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in two unrelated cases.

Created: 30 Sep 2019, 1:33 p.m. | Last Modified: 30 Sep 2019, 1:33 p.m.

Panel Version: 1.329

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Comment on list classification: Discussed in the Analysis & Interpretation meeting and decided to make this red for now.

Created: 25 Apr 2016, 12:18 p.m.

Comment on list classification: PMID: 26598328 describes the identification of biallelic variants in HSPA9 in three patients (two of which are siblings), with EVEN-PLUS syndrome (a proposed syndrome name), and discussed the evidence for likely effect on HSPA9 function due to its role as a mitochondrial chaperone.

Created: 15 Feb 2016, 11:46 a.m.

Comment on mode of inheritance: One patient was compound heterozygous, the two siblings were homozygous for a seperate mutation. Unaffected parents were heterozygous.

Created: 15 Feb 2016, 11:44 a.m.

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal